DK160559B - ANALOGY PROCEDURE FOR PREPARING 17ALPFA ACETYLENE DERIVATIVES OF ANDROSTEN COMPOUNDS - Google Patents

Description

- i -

DK 160559 B

The invention relates to an analogous process for the preparation of novel 17alpha-acetylene derivatives of androsten compounds of the general formula I of claim 1, and in particular such compounds of formula 5, wherein R represents an alkyl group of 1-12 carbon atoms and the dotted lines in A the ring represents an optional bond in the 1 (2) position under the condition that if the A ring is saturated, then R does not represent a methyl group.

In particular, among the alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n-octyl and 2,2-dimethyl hexyl and unsaturated aliphatic hydrocarbon groups such as vinyl, isopropenyl, isobutenyl or also allyl or 2-methylallyl. Among the compounds of formula I, libeta, 17beta-di-15-hydroxy-21-methylpregn-4-ene ~ 20-yn-3-one is a product just mentioned in United States Patent No. 3,793,308 which, incidentally, does not indicates physical data for the compound or any method of preparation thereof.

The other compounds of formula I are also novel compounds. While US Patent Nos. 3,127,428 and 3,221,033 disclose general formulas for starting products which comprise the compounds of Formula I, but these formulas are extremely broad and neither do the aforementioned patents predict or suggest the general formula cited above. In addition, they do not specify any method of manufacture.

In particular, the present invention relates to a process for the preparation of the compounds of claims 2-4.

In particular, among the compounds of formula I are mentioned: - 30-libeta, 17beta-dihydroxy-21-methylpregn-4-en-20-yn-3-one, - libeta, 17beta-dihydroxy-21-ethylpregn-4-en-20 yn-3-one, - libeta, 17beta-dihydroxy-21-methylpregna-1,4-dien-20-yn-3-one, - libeta, 17beta-dihydroxy-21-ethylpregna-1,4-dien-20 yn-3-one and libeta, 17beta-dihydroxy-21-isopropenylpregna-1,4-dien-20-yn-3-one.

It has been found that the compounds of formula I have interesting pharmacological properties. In particular, they have a - 2 -

DK 160559 B

remarkable anti-inflammatory effect by local pathway, which justifies their use as drugs.

The compounds of formula I exhibit a separation between anti-inflammatory properties by local pathway and by non-local pathway, which separation is very interesting as it allows the compounds of formula I to be used as drugs in doses where there is no need to fear classical cortisone-type side effects, in particular to control local inflammatory reactions such as edema, 10 dermatosis, pruritus and various types of eczema and sunburn. However, the compounds of formula I can also be used for the treatment of polyarthritis, arthrosis or lumbargia.

The compounds of formula I can be used to prepare pharmaceutical compositions containing as active ingredient at least one of said compounds of formula I.

These preparations can be used topically in topical application to the skin and mucous membranes.

These compositions may be solid or liquid and may be present in the forms commonly used in human medicine such as powder, pomade, cream, gel and aerosol preparations.

They may also be administered by the digestive or parenteral route and may be in the form of unsupervised or over-sugared tablets, cachets, capsules, granules, emulsions, syrups, suppositories and injectable aqueous solutions and emulsions.

These preparations are prepared according to the usual methods. The active ingredient may be incorporated therein together with additives commonly used in these pharmaceutical compositions such as talc, starch, aqueous or non-aqueous carriers, animal or vegetable origin fats, paraffin derivatives, glycols and various wetting, dispersing or emulsifying agents and preservatives.

In particular, the useful dose varies depending on the patient being treated and the disorder in question. It can e.g. lie between 1 and 4 applications per day of a pomade inside - 3 -

DK 160559 B

containing 0.1-5% of the product prepared according to Example 3.

Orally, it may be between 10 mg and 1 g of the product prepared according to Example 3 per ml. day.

The process according to the invention is characterized by the characterizing part of claim 1.

When K represents a ketal group, it is preferably a cyclic alkylene ketal group having 2-4 carbon atoms and in particular ethylene ketal or propylene ketal or also a dialkyl ketal such as e.g. dimethyl or diethyl ketal.

When K represents a ketone group which is blocked in the form of oxime, it is preferably a group of NOH or NOalc, where alc represents an alkyl group of 1-4 carbon atoms.

Y is preferably methyl, ethyl or n-propyl. Hal preferably represents a bromine atom.

The acid hydrolysis agent is preferably hydrochloric acid, sulfuric acid, acetic acid, citric acid or p-toluenesulfonic acid.

The dehydrogenation is preferably carried out by biochemical pathway and in particular by the bacterium Arthrobacter simplex UC 1047. The chemical route can also be used with chloranil 20 or other derivatives of p-benzoquinone such as 2,3-dichloro-5,6-dicyanobenzoquinone.

Thus, one can prepare libeta, 17beta-dihydroxy-21-methylpregn-4-ene-20-yn-3-one by subjecting either a compound of formula 11 ^ or a compound of formula 25 ιΐβ to the effect of a propynylmagnesium halide with formula

Hal-Mg-C = C-CH 3 and then the action of an acid hydrolysis agent to give libeta, 17beta-dihydroxy-21-methylpregn-4-en-20-yn-3-one. The preferred values for K, Y and Hal are the values given above.

In a preferred embodiment for the preparation of libeta, 17beta-dihydroxy-21-methylpregn-4-ene-20-yn-3-one is subjected to a 3-alk-oxy-11beta-hydroxyandrosta-3,5-dien-17-one , eg. 3-ethoxy-11beta-hydroxy-androsta-3,5-dien-17-one, the action of a propynylmagnesium halide, and then the resulting compound is subjected to the action of an acid hydrolysis agent, e.g. hydrochloric acid, to obtain

4 - DK 160559 B

the desired product.

In process variant b), as tertiary alcoholate, an alkali metal tert.-butylate or tert.-amylate, e.g. sodium, potassium or lithium tert.-butylate or 5-amylate.

The compounds of formula I wherein the ring A is saturated in the 1 (2) position are preferably prepared according to the first procedure.

The compounds of formula III used as starting products in the process of the invention are known compounds. They can be prepared according to the methods described in U.S. Patents 3,072,684 and 3,010,957.

The compounds of formulas 11 ^ and ΙΙβ are also 15 known compounds and can be prepared according to the process described in United States Patent 3,072,684.

5 DK 160559 B

The following examples illustrate the process of the invention while the preparation relates to an initial compound.

Preparation «5-ethoxy-116-h.vd roxyand ro s ta-3.5 -d one-17-on.

To 50 ° C, 43 g of 11β-hydroxyandrost-4-ene-3,17-dione prepared according to United States Patent 3,072,684, 215 ml of ethanol and 43 ml of 0.26 M solution of ethyl orthoformate are heated. Then 5.2 ml of a solution of 0.48 g of p-toluenesulfonic acid in 50 ml of ethanol is added. The resulting solution is kept for 5 minutes at 50 ° 0 and 10.6 ml of triethylamine are added, then cooled to 20 ° C. Then 258 ml of water is added. The reaction mixture is cooled for 1 hour to between 0 and 5 ° 0, filtered, washed with a mixture of ethanol, water and pyridine (50: 50: 0.5) to give 40.1 g of the desired product using.

Example 1.

lig .173-dihydrox.v-21-methylpregn-4-en-20-yn-5-one.

70 ml of 0.75 M solution of ethyl magnesium bromide in tetrahydrofuran is cooled to 0 ° C. The propylene is bubbled for 2 hours and allowed to warm to room temperature. 3.45 g of 3-eth-20-oxy-11g-hydroxyandrosta-3,5-diene-17-one and 14 ml of dry tetrahydrofuran are added. The reaction mixture is kept at 20-25 ° C for 45 minutes and poured into a 2N hydrochloric acid. It is extracted with ether, washed with water and dried. After purification of the obtained product, 11β, 17β - dihydroxy-21-methylpregn-4-ene-20-yn-3-one is obtained, mp, 223 ° C, Example 2.

113173-difaydrox.y-21-ethylpregn-4-en-20-yn-3-one.

65 ml of a 0.82 M solution of ethyl magnesium bromide in tetrahydrofuran is cooled to 0 ° C. You let the butyn bubble for 40 minutes and allow to warm to room temperature. 30 g of 3-ethboxy-11β-hydroxyandrosta-3,5-diene-17-one are added. Stir for 1 hour, pour into aqueous ammonium chloride, extract with ether, dry over sodium sulfate and evaporate the solvent under reduced pressure. Thus, after ehromatography on silica gel (eluent: benzene and ethyl acetate 8: 2 added 35 0.2 # triethylamine) 2.1 g of a product are treated with 25 ml of 1 N hydrochloric acid and 125 ml of methanol to give pour into a saturated sodium chloride solution and extract with methylene chloride,

6 DK 160559 B

dries over sodium sulfate and evaporates the solvent. There is thus obtained 1.62 g of crude product which is purified by ehrornatography on sillage 1 (eluent: benzene and ethyl acetate in a 1: 1 ratio).

Thus, 1.37 g of the desired product is obtained, m.p., 170 ° C and 5 a2 ° = + 49.5 ° + 2.5 ° (c = 0.59 +, chloroform).

Example 3

113.17 3-d ihy d roxy-21-methylpregna-1,4-d one-20-vin-3-one.

3.1 g of potassium tert-butylate are introduced into 50 ml of dioxane.

Propyne is bubbled through the resulting solution.

Then, 2 g of 11β-hydroxyandrosta-1,4-diene-3,17- -dione prepared in accordance with the method of U.S. Patent 2,902,498 and 25 ml of dioxane are added. Stir 5 hours at room temperature. Pour into 50 ml of acetic acid and water mixture (1: 3), dilute with 500 ml of water and extract with chloroform. The organic phase is washed with sodium bicarbonate and with water and dried. There is thus obtained 2.2 g of a product which is chromatographed on silica gel (eluent: chloroform and acetone in a ratio of 8: 2). 760 mg of a product with Ef = 0.24 is isolated which is purified by recrystallization from isopropyl ether. . Thus, 391 mg of the desired product is obtained with m.p. = -6.5 ° + 2 ° (c = 0.696, chloroform).

Example 4

113,173- dihydrox.v-21-ethylpregna-1,4-done-20-in-5-one.

Working as in Example 3 from Ιΐβ-hydroxyandro-25-ata-1,4, 4-diene-3,17-dione and 1-butyne gives the desired product with m.p. 192 ° 0, a2 ° = -6.5 ° + 1.5 ° (c = 0.696, CHCl3).

Example 5

113,173- dihydrox.v-21-isopropenylpregna-1,4-done-20-in-5-one.

Working as in Example 2 from Ιΐβ-hydroxyandrosta-1,2,4-diene-3,17-dione and isopropenylacetylene gives the desired product with m.p. 218 ° C, α2 ° = -20 ° + 1.5 ° (c = 0.896, CHCl3).

35 cepts:

Example 6

Example of pharmaceutical composition.

A pomade for topical application is prepared after re 7

DK 160559 B

Product prepared according to Example 1 1.5 S

additive ad 100 g details of additive: lanolin and vaseline.

Example 7.

Example of pharmaceutical composition.

A pomade for topical application according to the recipe is prepared: product prepared according to Example 3 0.5 g 10 additive per 100 g details concerning additive: lanolin and vaseline.

Example 8.

Example of pharmaceutical composition.

Tablets are prepared according to the recipe: product prepared according to Example 35 5 mg of additive to form a tablet of 350 mg of additive details: talc, starch, magnesium stearate.

20 Pharmacological study of 116,176-dihydroxy-21-methylpregn-4-en-20-yn-5-one (product A). of 116,173-dihydroxy-21-ethylpregn-4-ene-20-yn-3-one (product B) and IgG.176-dihydroxy-21-methylpregna-1,4-dien-20-yn-5-one (product C).

Products A, B and C are compared with hydrocortisone.

Compounds A, B and C and hydrocortisone are used in a common dispersant containing 0.25 # carboxymethyl cellulose and 0.20 # polysorbate 80, (registered trademark).

1. Examination of anti-inflammatory effect by oral route.1.

The anti-inflammatory effect is determined by the classical granuloma method.

In the technique used, which is a modification of the method of R. Meier et al. (Experientia, 1950, 6, 469), conventional Wistar female rats of 100-110 g receive an implantation of two cotton balls of 10 mg each under the thorax's skin. The oral treatment, which begins immediately after this implantation, lasts 2 days with two administrations per day. day. 16 hours after the last administration, ie

8 DK 160559 B

on the third day, the animals are killed.

The cotton balls surrounded by granular tissue formed, weighed in fresh condition and after storage for 18 hours at 60 ° C, the weight of the granuloma is obtained by subtracting the original weight of the cotton.

The results expressed in BA ^ q, ie. the dose causing inhibition of the granuloma of $ 50 is as follows: granuloma product A 50 mg / kg XO product B 50 mg / kg product C 8 mg / kg hydrocortisone 15 mg / kg

Conclusion.

Compounds A and B are much less active than hydrocortisone for inhibiting granuloma.

2, Examination of the dermic effect of compounds A. B and C. The dermic effect is determined by the croton edema sample. Croton edema trials:

The technique used is inspired by the technique according to 20 Tonelli et al. (Endocrinology 1965, 72, page 625): An edema is provoked in mice by the application of croton oil to an ear.

- On mice in a first team, apply the croton oil solution to the right ear.

- In mice of another team, apply the right ear croton-25 oil solution added to the product or hydrocortisone examined.

- You do not apply any product to the left ear of the mice.

After 6 hours you cut off the ears and weigh them.

The weight difference between the right ear and the left ear indicates the degree of inflammation.

The results are expressed in CA ^ q, dva. the active concentration, which by $ 50 reduces the edema caused by the croton oil on the test animals.

CA5Q in mg / ml compound A 0.6 compound B 0.6 compound C 0.08 hydrocortisone 2.5

Conclusion.

Compounds A and B, and in particular C, are much more active by local route than hydrocortisone.

- 9 -

DK 160559 B

Complementary pharmacological study of libeta, 17beta-di-hydroxy-21-methylpregna-1,4-dien-20-yn-3-one (product C).

Product C is compared with libeta, 17beta-dihydro-xy-pregna-1,4-dien-20-yn-3-one according to United States Patent Nos. 5,127,314 and 3,308,025, which is the closest known technique.

The compounds are used in an aqueous dispersant containing 0.25% carboxymethyl cellulose and 0.20% polysorbate 80 (registered trade mark).

10 1. Examination of anti-inflammatory effects by oral route.

The anti-inflammatory effect is determined by the classical granuloma method.

In the technique used, which is a modification of the method of R. Meier et al. (Experientia, 1950, 6, 469), conventional Wistar female rats weighing 100-110 g receive an implantation of two cotton balls of 10 mg each under the skin of the thorax.

The oral treatment that begins immediately after this implantation lasts 2 days with two administrations per week. day. 16 hours after the last administration, ie the third day, the 20 animals are killed.

The cotton balls are surrounded by granular tissue formed, weighed in fresh condition, and after storage for 18 hours at 60 ° C, the weight of the granuloma is obtained by subtracting the original weight of the cotton.

The results expressed in DA5Q, i.e. the dose causing an inhibition of the 50% granuloma is as follows: granuloma product C 8 mg / kg compound according to the United States inactive in the 30 patents 50 mg / kg

conclusion

Compound C is much more active than the known granuloma inhibition compound.

2. Investigation of the dermic effect of the compounds.

The dermic effect is determined by the croton sample.

DK 160559B

- ίο - edema.

Croton edema experiments: 5 The technique used is inspired by the technique according to

Tonelli et al. (Endocrinology 1965, 77, page 625): An edema is provoked in mice by the application of croton oil to an ear.

- On mice in a first hold, apply the croton oil solution to the right ear.

10 - On the mouse in another team, apply the right ear croton oil solution added to the tested product.

- You do not apply any product to the left ear of the mice.

After 6 hours you cut off the ears and weigh them. The weight difference between the right ear and the left ear indicates the degree of inflammation.

The results are expressed in CA ^ -q, i.e. the active concentration which by 50% reduces the edema caused by the croton oil on the test animals.

CA50 1 mg / ml Compound C 0.08 Compound of the United States Inactive in Patent Specifications 5.0 mg / kg

conclusion

Compound C is much more active by local route than the known compound.

Claims (6)

1. Analogous Process for the Preparation of 17alpha-Acetylene Derivatives of Androsten Compounds of General Formula I. T j ·····. CrCR (I) O where R represents an aliphatic hydrocarbon group having 1-12 carbon atoms and the dashed dashes in the A-ring denote an optional bond in the 1 (2) position, characterized by: a) a compound of formula II Ά QH ^ O V'N- ^ ΑΑΆ di ik '. wherein K represents a ketone group blocked in the form of ketal or oxime, 1Q or a compound of the formula equal to H0 UV. AAV yo - 12 - DK 160559 B where Y represents an alkyl group of 1-4 carbon atoms, action of an alkynylmagnesium halide of the formula Hal-Mg-C = CR where Hal represents a halogen atom and R represents an aliphatic hydrocarbon group of 1-12 carbon atoms , and then the action of an acid hydrolysis agent to give the corresponding compound of formula 1 wherein the R has the same meaning as above which, if desired, is subjected to the action of a dehydrogenating agent to -10 reaching the corresponding compound of formula Ιβ OH v / \ l_ / OH IJ * 'C = CR tx) I ^ hJ iab # o where R has the same meaning as above, or b) subjecting a compound of formula III HO H (xix) - 13 - DK 160559 B where the dotted line in the A-ring represents an optional bond in the 1 (2) position, effect of a compound of the formula HC = CR where R represents an aliphatic hydrocarbon group of 1-12 5 carbon atoms, in the presence of e t tertiary alcoholate to give the corresponding compound of formula I - OH I J '' MOR (!) H where R has the same meaning as above. Process according to claim 1, characterized in that the compounds of the general formula 10 I are prepared, wherein R represents a saturated or unsaturated hydrocarbon group of 1-12 carbon atoms and the dashed lines in the A-ring denote an optional bond in 1 ( 2) position under the condition that if the A-ring is saturated in the 1 (2) position, then R cannot denote a methyl group. Process according to claim 1, characterized in that the compounds of formula I are defined as in claim 2 which are saturated in the 1 (2) position. Process according to claim 1, characterized in that the compounds of formula I are defined as in claim 2 which are unsaturated in the 1 (2) position. 5. A process according to claim 1, characterized in that - the preparation of - libeta, 17beta-dihydroxy-21-ethylpregn-4-ene-20-yn-3-one, - libeta, 17beta-dihydroxy-21-ethylpregna-1,4 -di-20-yn-3-on or 25. Ubeta, 17beta-dihydroxy-2l-isopropenylpregna-1,4-dien-20-yn-3-one. Process according to claim 1, characterized in that the preparation of libeta, 17beta-dihydroxy-21-methyl-pregna-1,4-dien-20-yn-3-one is prepared.